Abstract
Epstein-Barr virus (EBV) infection and latency has been associated with malignant diseases including nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and immune deficiency associated lymphoproliferative diseases. EBV-encoded latent membrane protein 2A (LMP2A) recruits Lyn and Syk kinases via its SH2-domain binding motifs, and modifies their signaling pathways. LMP2A transgenic mice develop hyperproliferative bone marrow B cells and immature peripheral B cells through modulation of Lyn kinase signaling. LMP2A/λ-MYC double transgenic mice develop splenomegaly and cervical lymphomas starting at 8. weeks of age. We reasoned that targeting Lyn in LMP2A-expressing B cells with dasatinib would provide a therapeutic option for EBV-associated malignancies. Here, we show that dasatinib inhibits B cell colony formation by LMP2A transgenic bone marrow cells, and reverses splenomegaly and tumor growth in both a pre-tumor and a syngeneic tumor transfer model of EBV-associated Burkitt lymphoma. Our data support the idea that dasatinib may prove to be an effective therapeutic molecule for the treatment of EBV-associated malignancies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 49-56 |
| Number of pages | 8 |
| Journal | Antiviral Research |
| Volume | 95 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2012 |
Funding
R.L. was supported by Public Health Service grants CA133063 and CA73507. K.F. was in part supported by the Viral Replication Training Program (T32-AI060523) and J.D. was supported in part by T32-CA079447 from the National Institutes of Health National Cancer Institute and by the Washington Square Health Foundation. This work was also supported by the Northwestern University Interdepartmental ImmunoBiology Flow Cytometry Core Facility.
Keywords
- Burkitt lymphoma
- Dasatinib
- Epstein-Barr virus (EBV)
- Latent membrane protein 2A (LMP2A)
- Lyn
- Post-transplant lymphoproliferative diseases (PTLD)
ASJC Scopus subject areas
- Virology
- Pharmacology